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A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude

  1. Author:
    Choi, Y. S.
    George, C.
    Comin, M. J.
    Barchi, J. J.
    Kim, H. S.
    Jacobson, K. A.
    Balzarini, J.
    Mitsuya, H.
    Boyer, P. L.
    Hughes, S. H.
    Marquez, V. E.

  2. Author Address

    NCI, Ctr Canc Res, Med Chem Lab, 376 Boyles St,Bldg 376,Rm 104, Frederick, MD 21702 USA NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA Katholieke Univ Leuven, Rega Inst, B-3000 Louvain, Belgium NCI, Expt Retrovirol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA NCI, HIV Durg Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA Marquez VE NCI, Ctr Canc Res, Med Chem Lab, 376 Boyles St,Bldg 376,Rm 104, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Journal of Medicinal Chemistry
    1. 46
    2. 15
    3. Pages: 3292-3299
  4. Type of Article: Article
  1. Abstract:

    The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU- catalyzed olefination reaction. Mitsunobu coupling with N-3- benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70degrees away from a perfect N (P = 0degrees) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (v(max)) of N-MCD4T to 6.81degrees, and the superposition of both structures showed a RMS deviation of only 0.039 Angstrom. The combined structural analysis of P and vmax shows that while the value of P may differ substantially, the low v(max) resolves the differences and becomes the dominant pseudorotational. parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC50 than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.

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